Positional cloning of mouse coat color mutations has provided a foundation for identifying and understanding paracrine signaling pathways that play fundamental roles in biology and disease. The phenomenon known as pigment-type switching-whereby hair follicle melanocytes switch between the production of red/yellow pheomelanin vs. black/brown eumelanin-has been especially informative for pathways used by the neuroendocrine, adrenal, exocrine, and pigmentary systems because of the central role played by the Melanocortin 1 receptor. Large-scale efforts in chemical mutagenesis and reverse genetics are gradually saturating the potential of the laboratory mouse as a tool for gene discovery, but advances in genomic technology have extended the reach of forward genetics beyond traditional model organisms. Although the pathways are evolutionarily conserved, the sensitivity of color variation as a phenotypic readout coupled with the opportunity to observe and select for unusual mutations in companion and domestic animals provides additional opportunities. The current proposal focuses on two classical coat color mutations in non-model organisms, Orange in the domestic cat and Sex-linked yellow (Sly) in the Syrian hamster; these are especially interesting because they are X-linked, yet mimic a loss-of-function mutation in the autosomal Melanocortin 1 Receptor (Mc1r). Our preliminary studies have identified a candidate mutation and mechanism for Orange, and a genetic map position and positional cloning strategy for Sly. Additional knowledge about the genetics and biology of melanocortin signaling will come from: (1) Experimental genetic studies in cultured cells and in transgenic animals to experimentally confirm and explore the molecular pathophysiology of Orange; and (2) Molecular identification and characterization of the hamster Sly mutation.